Introduction to Toxicology

Toxicology

• Toxicology studies the unwanted harmful effects of drugs and chemicals.
• A poison is any substance that can harm a living organism.
• Almost all drugs have a threshold dose beyond which they become poisonous.
• Even excess carbohydrates can be harmful.
• Paracelsus stated, "All things are poison, and nothing is without poison. Solely the dose determines that a thing is not a poison".
• About 2 million hospitalized patients experience adverse drug reactions annually in the U.S.
• About 100,000 of these are fatal.
• Dosing errors affect an estimated 775,000 people annually, costing $1.5 to $5.5 billion.

Types of Effects

• Effects can be desirable or undesirable.
• Undesirable effects can be non-deleterious (side effects) or deleterious (toxic effects).

Pharmacological Toxicity

• Pharmacological toxicity is an extension of a drug's therapeutic effect due to increased dose or duration of treatment.
• Type A reactions are expected from a drug's pharmacological actions.
  • Examples include central nervous system depression from high doses of barbiturates and a severe drop in blood pressure from high doses of sodium nitroprusside. Also, extrapyramidal motor disorders can occur from prolonged use of certain antipsychotics.

Pathological Toxicity

• Pathological toxicity manifests as pathological effects in the body.
  • Example: Liver damage from acetaminophen overdose.
  • Another example is the antifungal drug amphotericin B and the antibiotic gentamicin, which can cause kidney damage.
• Genotoxicity damages DNA, caused by drugs, chemicals, ionizing radiation damaging DNA.
  • Examples include nitrogen mustards, nitrosoureas, alkyl sulfonates, and cisplatin.

Mechanisms of Drug Toxicity

• On-target effects result from drug binding to intended receptors, but at inappropriate concentrations or kinetics or in wrong tissues.
  • Example: Sedative effects from antihistamines binding to wrong receptors.
• Off-target effects occur when drugs bind to unintended receptors.
  • Example: Disruption of potassium channels leading to cardiac arrhythmias.
  • Off-target binding can also happen when receptors, normally for specific organ/tissue, are inappropriately targeted.

Hypersensitivity Reactions (Type B)

• Hypersensitivity reactions (Type B) are mediated by the immune system.
  • Four types exist:
    • Type I (Immediate): IgE-mediated, rapid onset. (e.g. penicillin)
    • Type II (Cytolytic): Antibody-mediated destruction of cells (e.g., some blood disorders)
    • Type III (Immune Complex): Immune complex deposition in tissues (e.g., serum sickness)
    • Type IV (Delayed): T-cell-mediated, delayed onset (e.g., contact dermatitis)

Poisoning Cases

• Common substances associated with poisonings.
• Reasons for these cases are medication errors, drug interactions etc.